Preparation of 11-oxygenated delta5-3-ethylenedioxy-20-keto-17-isopregnenes



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United States Patent PREPARATION OF ll-OXYGENATED A -3-ETHYL-ENEDIOXY-Z0-KETO 17-IS0PREGNENES Lewis H. Sarett, Princeton, NJ., andWilliam F. Johns, Morton Grove, Ill., assignors to Merck & Co., Inc.,Rahway, N.J., a corporation of New Jersey No Drawing. ApplicationJanuary 8, 1957 Serial No. 632,975

3 Claims. (Cl. 260239.55)

This invention relates to cyclopentanopolyhydrophenanthrene compoundsand processes of obtaining the same. More particularly, it is concernedwith a novel process for converting polyhydrophenanthrene compounds tocyclopentanopolyhydrophenanthrene compounds. Specifically, it isconcerned with the preparation of dl-ll-keto progesterone anddl-ll-hydroxy progesterone and novel polyhydrophenanthrene compoundsuseful .in preparing the same. i t t I This application is acontinuation-impart of our copending application Serial No. 310,134,filed September 17, 1952,.now United States Patent 2,786,064, issuedMarch 19, 1957. a a

The preparation of steroid substances by total sy thesis involvingtheformation of the four ring system, the introduction of angular methylgroups at positions and 1'3, and the placing of desired functionalsubstituents in. the ring system presents a formidable challenge. Inaddition to these difiiculties, the problem is further complicated bythe stereochemistry of steroidal substances. Thus, saturated steroids,with'a of six asymmetric centers, are capable of existing in at leastsixty four stereochemical modifications. However, in view of thetherapeutic value and importance of steroids such as cortisone and thelike, and the scarcity of raw materials suitable for use as startingmaterials in the preparation of cortisone and related compounds, effortshave been made to prepare these compounds by total synthesis.-

It is .an object of thepresent invention to provide a new method forconverting polyhydrophenanthrene com pounds to1,2-cyclopentanopolyhydropheuanthrene compounds; thereby making possiblethe preparation of ster-. oids bytotal synthesis.

Another object is to provide a novel process for the preparation ofdl-ll-keto progesterone and-dl-ll-hydroxy progesterone from functionallysubstituted dodecahydrophenanthrene compounds.

An additional object is to provide novel dodecahydrophenanthrenecompounds which are useful as intermediates in the synthesis ofdl-11-keto progesterone and d1- ll-hydroxy progesterone.

Other objects will be apparent from the detailed description of ourinvention hereinafter provided.

In accordance with our invention, we have found thatpolyhydrophenanthrene compounds having in ring C a methallyl substituentat position 2 and a carboxymethyl or esterified carboxymethylsubstituent at position 1 can be treated to eifect ring closure, therebyforming ring D of the steroid skeleton and providing a functionalsubstituent at position 17, Our process for effect-ing this ring closureand the formation of a -keto pregnane compound can beshown by thepartial formulas as follows: I

2,909,519 PatentedOct'. 20,

V omom-o-som, onionr-o-soni,

your

wherein R represents hydrogen, an alkyl radical, an aryl radical, or anaralkyl radical, and R represents an alkyl radical, an aryl radical oran aralkyl radicals In accordance with the foregoing flow sheet, thestarting polyhydrophenanthrene compound having a methallyl substituentat C-2 and a carboxymethyl or esterified carboxymethyl substituent at0-1 (I) is reacted with an alkali or an alkaline earth metal or analkali or alkaline earth metal aluminum hydride to form thecorresponding primary alcohol (II). This latter compound is then treatedwith an organic sulfonyl halide in the presence of a tertiary amine toformthe sulfonic acid ester (III). In the next step of our process, thesulfonic acid ester is oxidized to convert the Z-methallyl substituentinto an acetonyl substituent and form compound IV. Upon intimatelycontacting compound IV with an alkali, ring closure is effected to formthe 20-keto-steroid compound (V).

Alternatively, as will be apparent to those skilled in the art, theorder of carrying out these reactions can be varied. Thus, the oxidationof the methallyl substitu entto form the acetonyl compound can beeffected prior to the formation of the sulfonate derivative if desired.However, we have found that the sequence of the reactions shownpreviously is most satisfactory.

The processes described above can be used to convert saturated orunsaturated polyhydrophenanthrene compounds having in ring C thesubstituents depicted above to the corresponding steroid compounds. Inaddition, the starting polyhydrophenanthrene compounds can also haveother functional substituents such as keto groups or protected hydroxylgroups in rings A, B or C of the starting polyhydrophenanthrenecompound. When this method is utilized in the preparation of a steroidhaving angular methyl groups at positions 10 and 13,polyhydrophenanthrenes having methyl substituents at positions 2 and 4bare employed as starting materials.

Thus, pursuant to a further embodiment of our invention, theabove-described procedures may be utilized in the preparation ofdl-ll-keto progesterone from 2,4bdimethyl 1carboxymethyl-Z-methallyl-7-ethylenedioxy- 1,2,3,4,4a,4b,5,6,7,8,10,1021dodecahydrophenanthrene- 4-01, or the corresponding compound having an'es'terified carboxymethyl substituent in place of the carboxymethylgroup. These reactions may be shown as follows:

CH CH HO -CHg-(il=CHa HO CHz-(E=CH2 -CH2CO OR 431120112011 (V (VI CH;110 CHr =oHg OHgOHgOSOzR 0 (VIII) (EH: 0 -CHrC=OHg CHZ- H2O 2 I [O 0(XII) HO CH2O 0 CH3 CHCHOSOR I 0 --CH2 C O C H! 'GHZCHBOSOZRl (XIII) CH;$11; $0 C O 0 H0 i 0 I I o I DC O I O (XIVA) (X l p l 4 O 5 it? in (X1B) OCH i COCH n HO n oi fi wherein R represents hydrogen, and alkylradical, an aryl radical, or an aralkyl radical, and R represents analkyl, aryl, or aralkyl radical.

Thus, in accordance with the foregoing reaction scheme, the startingcompound, 2,4b-dimethyl-1-(carboxymethyl) 2 methallyl 7 ethylenedioxy1,2,3,4, 4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol, or thecorresponding compound having an esterified carboxymethyl substituent(VI), is first reduced to form the corresponding primary carbinol (VII).This reduction is readily etfected by intimately contacting compound VIwith an alkali or an alkali metal aluminum hydride or the free metal ina suitable inert reaction medium (inter alia dioxane, tetrahydropyran,tetrahydrofuran, a lower alkanol and the like). For example, thereduction is conveniently carried out by reacting compound VI withlithium aluminum hydride in tetrahydrofuran at room temperature forsuflicient time to complete the reaction. The reduction can be effectedin shorter time by heating the reactants at temperatures up to about C.After the reduction with the lithium aluminum hydride is complete, thedesired product is readily recovered by adding water to the reactionmixture, filtering, and evaporating the filtrate-under diminishedpressure.

As indicated above, dodecahydrophenanthrene com pounds having either al-carboxymethyl substituent or an esterified carboxymethyl substituentcan be reduced in accordance with our process to obtain thecorresponding dodecahydrophenanthrene compound having at position 1 a2-hydroxyethyl substituent, Lower alkyl esters such ascarbomethoxymethyl, carboethoxymethyl, and

carbopropoxymethyl which are readily prepared are most convenientlyreduced by our process.

In the second step of our process, the1-(2-hydroxyethyl)-dodecahydrophenanthrene compound is converted to thecorresponding sulfonic acid derivative (VIII) by reaction with an alkyl,aryl, or aralkyl sulfonyl halide in the presence of a tertiary amine. Incarrying out this reaction we usually prefer to form the tosylderivative by reacting 2,4b-dimethyl-1-(Z-hydroxyethyl) 2 methallyl- 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol(VII) with para toluene sulfonyl chloride in the presence of pyridinesince maximum yields of the tosyl derivative are usually obtained underoptimum conditions. However, other sulfonyl halides such as a methanesulfonyl halide, a benzene sulfonyl halide, and the like can be used toobtain the corresponding sulfonic acid derivatives. Similarly, othertertiaryamines such as picoline, trimethyl amine, and the like aresuitable reaction mediums forthis condensation. After the reaction iscomplete, the "sulfonic acid ester is readily recovered by diluting thereaction mixture with water and extracting the product from the aqueoussolution with a water immiscible solvent'such asether.

The hydroxy-l substituent at C-,4'of compound VIII can, if desired, beoxidized at this point of the overall process to form the correspondingll-keto compound (XII); We have found that this oxidation is readilyeifected'by reacting compound VIII with a chromic anhydride-pyridinecomplex in pyridine. The oxidized product is recovered by diluting thereaction mixture With water, extractingthe aqueous solution with a waterimmiscible solvent, such as ether, and concentrating the solvent extractunder diminished pressure. The residue so obtained can be furtherpurified by chromatography over acid washed alumina. In the next step ofour process, the methallyl side chain at C-2in compounds VIII and XII isoxidized to convert this substituent to an acetonyl radical, therebyforming compounds IX and XIII. This oxidation of the methallylsubstituent can be elfected inseveral ways. Thus, the oxidation can becarriedout by reacting compound VIII or compound XII with osmiumtetroxide and decomposing the osmate ester to form the correspondingglycol which on treatment with a glycol splitting agent such as periodicacid, lead tetraacetate, and the like yields the acetonyl compound.Alternatively, the preparation of the acetonyl substituteddodecahydrophenanthrene' compound is effected by intimately contactingcompoundsVIII and XII with ozone, and decomposing the resulting ozonidederivative with a suitable reducing agent to form compounds IX and XIII,respectively.

Alternatively, as indicated above, compound VII and the corresponding4-keto compound can be oxidized to form the corresponding acetonylcompounds which can then be reacted with the sulfonyl halide'to obtaincompounds IX and XIII, respectively.

The ring closure of compounds IX and XIII to form ring D of the steroidcompounds is brought about by intimately contacting these compounds witha base, such as triethylamine, an alkali metal, an alkali metalalkoxide, an alkali metal hydride, or an alkaline eanth metal alkoxide(inter alia, sodium, potassium, sodium methoxide, potassium tertiarybutoxide, sodium isopropoxide, sodium hydride, and the like). Thereaction is conveniently carried'out in a suitable solvent medium such alower alkanol, benzene, toluene, ether or the like. Generally, we preferto effect this ring closure by reacting compound IX or compound XIIIwith a sodium or potassium alkoxide in a lower alkanol, since thesereactants are readily available and their use results in good yields ofthe desired steroid compounds. Thus, the ring closure is convenientlyeffected by reacting compounds IX or XIII thioketal derivative for thispurpose.

the resulting reaction mixture with water, extracting the 6 on, n11, i I430 7 CO Iso form Normal form V The pregnene compounds XIVB and XBsoobtained may be hydrolyzedbyreaction with acid to cleave .the protectingethylenedioxy' substituent and regenerate the 3-keto substituent,thereby forming compounds XV (dlll-keto progesterone). and XI(dl-ll-hydroxy progesterone), respectively, in which the double bondis'shifted to the 4,5 position. Alternatively, as will be readily apparentto those skilled in the art, the other intermediate products, namely,VII-XIVB, can be similarly hydrolyzed, for example, by reaction withhydrochloric acid, perchloric acid, p-toluene sulfonic acid and thelike, to cleave the ethylenedioxy group and obtain the correspondingketo compound. Further, compound XI (dl-ll-hydroxy progesterone) can beconverted by oxidation, for example, by treatinent with chromicoxide-pyridine complex, to dl-ll-keto progesterone (XV).

The novelcompounds of the present invention are useful in thepharmaceutical field and serve as intermediates in the preparationofadrenal cortical hormones, such as ll-dehydrocorticosterone (KendallsCompound A), cortisone;hydrocortisone, and ,the like. Thus, dl-ll-ketoprogesterone and the derivatives thereof are useful as intermediates inthe preparation of cortisone, and cortisone-like compounds. Similarly,dl-ll-hydroxy progesterone and derivatives thereof can be utilized asintermediates in the preparation of -cortisone, hydrocortisone, andother steroi compounds having cortisonelike activity.

In the foregoing reaction sequence specifically illustrating theprocesses of our invention, we have employed the ethylenedioxyderivatives, although other cyclic ketal derivatives can be similarlyused in our process. In general, we have found the lower alkylenedioxyderivatives wherein the hydrocarbon group contains not more than sevencarbon atoms such as the ethylenedioxy, trimethylenedioxy,propylenedioxy and butylenedioxy derivatives are most suitable incarrying out the processes 'of our invention. However, in place of usinga lower alkylenedioxy substituent to block or protect the-'ketosubstituent, We'can use other derivatives readily hydrolyzable to keto,such as an enol ether monothioketal, or a di- The examples which followare presented methods of carrying out our process.

EXAMPLE 1 to illustrate 2,4b-dim ethyl-1-(Z-hydroxyethyl)-2-methallyl-7-ethylenedioxy-J,2,3,4,4a,4b,5,6,7,8,9,10,10a-dodecahydrophenanthrene-4-olVII) A solution of 2.58 g. of the 'stereoisomeric form of2,4b-dimethyl-1-( l-carbomethoxymethyl) -2-methallyl 7- ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol, melting at157-8 C., which may be prepared as described in copending applicationSerial No. 310,133, filed September 17, 1952, in 200 ml. absolutetetrahydrofuran was added to a solution of 0.80 mg. lithium aluminumhydride in 8 ml. tetrahydrofuran. The mixture was then stirred for 20hours after which time the excess hydride was decomposed with water. Thereaction mixture was then filtered, dried, and concentrated in vacuo toa crystalline residue of 2,4b-dimethyl-l-(2- hydroxyethyl)-2-methallyl-7-ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,l0,10a-dodecahydrophenanthrene-4-ol. The product wasrecrystallized from benzene and found to exist 7 in two crystallinemodifications, one melting at ZOO-1 C., and a second at 210-211 C.

A solution of 10 mg. of VII, M.P. 210-211 C. dissolved in 1 ml. oftetrahydrofuran and 0.5 ml. of 3 M perchloric acid solution was preparedand allowed to stand for 4 hours at room temperature. At the end of the4 hour period the reaction mixture was neutralized with aqueouspotassium bicarbonate solution. The product2,4b-dimethyl-1-(2-hydroxyethyl)-2-methally1-7-keto-1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene- 4-01, M.P. 153155C. is obtained by extraction with chloroform, evaporation of'thechloroform extracts, and crystallization of the resulting residue fromethyl acetate.

EXAMPLE 2 2,4b-dimethyl-1-(-Z-hydroxythyl)-2- methallyl 7 ethylenedioxyl,2,3,4,4iz,4b,5,6,7,8,10,1001 dodecahydrophenanthrene-4-0l (VII) Asolution of 2.54 g. of 2,4bdimethyl-1-(l-carboxymethyl)-2-methallyl-7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-ol, melting point 250-1 C., whichmay be prepared as described in copending application Serial No.310,133, filed September 17, 1952,'in 0.50 1. absolute tetrahydrofuranwas added to a refluxing solution of'2.5 g. lithium aluminum hydride in25. ml. tetrahydrofuran. The solution was stirred at reflux temperaturefor 30 minutes. At the end of this time the reaction mixture wasquenched with water,'and the product isolated'as described in Example 1.

EXAMPLE 3 2,4b dimethyl-I-(2-tosyl0xyethyl) -2-mthallyl-7-elhylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-401(VIII).

To an anhydrous solution of 302 mg. of 2,4b-dimethyl- 1-(2-hydroxyethyl)2-methallyl-7 ethylenedioxy-1,2,3, 4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 01 (VII) in pyridine was added 168 mg. of purep-toluene sulfonyl chloride. The mixture was allowed to stand at roomtemperature for about 20 hours after which time the excess tosylchloride was decomposed with a few drops of aqueous sodium bicarbonate.The solution was then diluted with water and extracted with ether. Theorganic extract was concentrated to dryness in vacuo. Pure2,4b-dimethyl-1- (2-tosyloxyethyl)-2-methallyl 7-ethylenedioxy-l,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol(VIII), M.P. 1578 C., was obtained from the crystalline residue byfractional crystallization from a mixture of benzene and petroleumether.

In another experiment starting with 2.47 g. of compound VII and' 1.48 g.of p-toluene sulfonyl chloride, the reaction was successfully run withthe temperature of the reaction mixture held at C. for about 20 hours.

Upon hydrolysis of compound VIII with acid the ethylenedioxy group iscleaved to obtain 2,4b-dimethyll-(2 tosyloxyethyl) 2- methallyl 7 keto1,2,3,4,4a, 4b,5,6,7,9,10,l0a-dodecahydrophenanthrene-4-ol.

EXAMPLE 4 2,4b dimethyl-I-(2-t0.s'yl0xyethyl)2-methallyl-7-ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10ad0decahydr0phenanihrene-4-0ne (XII) 160 mg. of 2,4b-dimeth'yl-1-(2-tosyloxyethyl)-2- methallyl7 ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol in 1 ml. ofanhydrous pyridine was added to a solution of 160 mg. chromic anhydridein 1 ml. pyridine. The mixture was allowed to standat room temperaturefor 16 hours after which time it was diluted with water and extractedwith ether. The ether extract was washed with water, dried, andconcentrated to dryness in vacuo. A solution of the crystalline residuein a mixture of benzene and petroleum ether was chromatographed overacid washed alumina. Elution with ether yielded pure2,4b-dimethyl-1-(2-t0syloxy :ethyl)-2-methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,

- 8 7,8,10;10a-dodecahydrophenanthrener4-one (XII), M.P. 156,-8" C.

Upon hydrolyzing compound XII with an acid such as perchloric acid, theethylenedioxy substituent is cleaved to obtain2,4b-dimethyl-1-(2-tosyloxyethyl)-2-methallyl-7-keto-1,2,3,4,4a,4b,5,6,7,9,10,10a dodecahydrophenanthrene-4-on'e. 1

' EXAMPLE 5 2,4b-dimethyl-1-(2-tosyloxyethyl) 2 acetonyl-7-ethylenedioxy-I,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-0ne (XIII) To 445mg. 2,4b-dimethyl-1-(2-tosyloxyethyl)-2- methally1-7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-one dissolved in 5ml. benzene was added 208 mg. osmium tetroxide. The solution was allowedto stand at room temperature for one hour. Seven ml. of ethyl alcoholand a solution of 0.7 g. sodium sulfitein 4 ml. Water were then addedand the solution shaken for twenty minutes. The upper organic layer wasthen decanted and filtered, while the lower layer was washed with ethylalcohol. The alcohol was also filtered and combined with the upperorganic layer. The benzene-alcohol solution containing the desiredproduct was then concentrated in vacuo to one-tenth the original volume.The concentrate was diluted with water and extracted with chloroform.The chloroform extract, after being washed and dried, was concentratedto dryness in vacuo to give2,4b-dimethyl-1(2-tosyloxyethyl)-2-(2,3-dihydroxy-2-methyl) propyl 7ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-oneas an amorphous solid.

This material was dissolved in 4 ml. methyl alcohol and 1 ml. pyridine,and to this solution was added 250 mg. of periodic acid in 0.5 ml.water. The mixture was allowed to stand at room temperature for 30minutes, diluted with water and extracted with chloroform. The organicextract was washed, dried, and concentrated in vacuo to an oil.Chromatography over acid washed alumina and elution with ether, yieldedthe desired product,2,4b-dimethyl-l-(2-tosyloxyethyl)-2-acetonyl-7-ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-one (XIII), M.P.104-8 C. (d.).

The above osmylation reaction was also successfully carried out in a 9:1benzene-tetrahydrofuran solution utilizing 7.84 g. of compound XII and4.8 g. osmium tetroxide. When compound XIII is subjected to acidhydrolysis, for example, by treatment with perchloric acid, theethylenedioxy substituent is cleaved and 2,4b-dimethy1-1-(2-tosyloxyethyl) 2 acetonyl 7 keto 1,2,3,4,4a,4b,5,6,7,9,l0,10a-dodecahydrophenanthrene-4-one is obtained.

EXAMPLE 6 A -3-ethylenedi0xy-11,20diket0-17-isopregnene (XI VA To asolution of mg. of 2,4b-dirnethyl-1-(2-tosyloxyethyl) -2-acetonyl-7ethylenedioxy-1,2,3,4,4a,4b,5,6,7,8,10,10a-dodecahydrophenanthrene-4-one in 1 ml. methyl alcohol wasadded 0.08 ml. of a 2 N solution of sodium methoxide in methyl alcohol.The solution was allowed to stand in a closed flask at room temperaturefor one hour after which time it was diluted with water and extractedwith chloroform. The chloroform extract was washed, dried, andconcentrated in vacuo. The crystalline residue so obtained waschromatographed on alumina. Elution with a mixture of ether-petroleumether yielded A 3-ethylenedioxy-1l, 20-diketo-17-isopregnene (XIVA),M.P. 212-5" C., which on hydrolysis with acid yields A-3,1l,20-triketo-l7-isopregnene.

EXAMPLE 7 A -3-ethylenedioxy-I1,20-diket0-I 7 -is0pregnene X I VA To asolution of 80 mg. of 2,4b-dimethyl-1-(2-tosyloxyethyl) 2 acetonyl 7ethylenedioxy 1,2,3,4,4a,4b,5,-6,7,8,I0,10a-dodecahydrophenanthrene-4-one in 1.5 ml. of

benzene was added 0.15 ml. of a 1 M solution of potassium tertiary.butoxide in tertiarybutyl alcohol. This mixture was then stirred for 20hours at room temperature. It was then diluted with water and extractedwith chloroform. vThe chloroform extract was washed, dried, andconcentrated under reduced pressure to produce a crystalline residue.The crystalline material was dissolved inla mixture of benzene andpetroleum ether, chromatographed on acid washed alumina. From theether-petroleum ether eluate was obtained crystalline AB-ethylenedioxy-l 1,20-diketol7-isopregnene (XIVA) EXAMPLE 8 A-3ethylenedi0xy-11,20-diketo-pregnene (XIVB) A solution of 165 mg. A-3-ethylenedioxy-l1,20-diket0- 17-isopregnene in 5 ml. benzene and 2 ml.methyl alcohol was treated with 3 ml. 2 N methanolic sodium methoxide.The solution was allowed to stand at room temperature for 2 hours. Itwas diluted then with water, and extracted with chloroform. Thechloroform extract was washed, dried, and concentrated in vacuo, givinga crystalline residue which yielded, after chromatography in the mannerpreviously described, A -3-ethylenedioxy11,20- diketo-pregnene (XIVB),M.P. 181.0182.5 C.

The above epimerization was also carried out using potassium carbonatein place of sodium methoxide.

When A -3-ethylenedioxy-11,20-diketo-pregnene is subjected to acidhydrolysis by treatment with an acid such as perchloric acid, theethylenedioxy substituent is cleaved and dl-ll-keto progesterone (XV) (N-3,11,20- triketo pregnane), is obtained.

EXAMPLE 9 2,4b dimethyl- 1 -(2 tosyloxyethyl) 2 acetonyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene 4 ol (IX) To 910mg. of 2,4b-dimethyl-l-(2-tosyloxyethyl)-2- methallyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,- lOa-dodecahydrophenanthrene-4-ol dissolved in9 ml. of benzene and 2 ml. of tetrahydrofuran was added 545 mg. osmiumtetroxide. The solution was allowed to stand at room temperature for 30minutes after which time 12 ml.

of ethanol and a solution of 1.2 g. sodium sulfite in 7 ml.

of water were added. The solution was then shaken for 25 minutes and theproduct, 2,4b-dimethyl-l-(2-tosyloxyethyl) 2 (2,3 dihydroxy 2 methyl)propyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene-4-ol recovered in the same manneras described inExample 5 for the corresponding 4-keto compound. V

0.84 gram of 2,4b-dimethyl-l a-tosyloxyethyl)-2-(2,3- dihydroxy 2methyl) propyl 7 ethylenedioxy l,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrene 4 o1, dissolved in 8 ml. methanol and 2.2 ml.pyridine, was mixed with a solution of .61 g. periodic acid in 1.5 ml.of water. The mixture was allowed to stand at room temperature for 30minutes, water added and the mixture extracted with chloroform. Onremoval of the chloroform there was obtained a residue containing2,4b-dimethyl 1 (2 tosyloxyethyl) 2 acetonyl 7 ethylenedioxyl,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydrophenanthrene-4-ol.

EXAMPLE 10 A -3-ethylenedi0xy-11-hydr0xq-20-ket0 pregnene and A3-ethylenedioxy-11 -hydroxy-20-ket0-is0pregnene A solution of 760 mg. of2,4b-dimethyl-1-(2-tosyloxyethyl) 2 acetonyl 7 ethylenedioxy1,2,3,4,4a,4b,5,- 6,7,8,10,lOa-dodecahydrophenanthrene-4-ol in 5 ml. ofmethanol and .80 ml. of a solution of 2 N sodium methoxide in methanolwas allowed to stand for 20 hours at room temperature. The resultingmixture was diluted with water, extracted with chloroform and thechloroform solution dried. After removal of the chloroform by 7 10distillation under reduced pressure, there was obtained a mixture of A-3-ethylenedioxy-ll-hydroxy-ZO-keto "pregnene (XA) and A-3-ethylenedioxy-1l-hydroxy-ZO-ketoisopregnene (XB), M.P. 182-93 C.

The mixture of A -3-ethylenedioxy-1l-hydroxy-20-keto pregnene (XA) and A-3-ethylenedioxy-11-hydroxy-20- keto-isopregnene (XB) of M.P. 182193 C.,was dis-.

solved in acetone, a small amount of p-toluene sulfonic acid added andthe solution heated at reflux temperature for 20 minutes. The productwas recovered by adding water to the reaction mixture, extracting withchloroform, washing the chloroform extract with water, drying theextract and evaporating to dryness. The resulting solid was crystallizedfrom ethyl acetate to give a crystalline product, M.P. -200 C. which isa mixture of A -3,20 diketo-l l-hydroxy-pregnene (XI), (dl-ll-hydroxyprogesterone), and A -3,20-diketo-ll-hydroxy-isopregnene.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changw and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

What is claimed is:

l. The process which comprises intimately contacting wherein Rrepresents a hydrocarbon radical having one to seven carbon atoms, Rrepresents a member from the group consisting of keto and hydroxyl and Rrepresents a lower alkylene group, with an alkali metal alkoxide toproduce a compound of the formula:

2. The process which comprises intimately contacting 2,4b dimethyl l (2tosyloxyethyl) 2 acetonyl 7 ethylenedioxy 1,2,3,4,4a,4b,5,6,7,8,10,10adodecahydrophenanthrenet-ol with an alkali metal alkoxide to form acompound of the formula:

ZZZ, HO to? 3. The process which comprises intimately contacting 2,4bdimethyl l (2 tosyloxyethyl) 2 acetonyl 7 ethylenedioxy1,2,3,4,4a,4b,5,6,7,8,10,10a dodecahydro- 11 phenanthrene-4-one with analkali metal alkoxide'to form a compound of the formula:

References Cited in the file of this patent UNITED STATES PATENTS

1. THE PROCESS WHICH COMPRISES INTIMATELY CONTACTING A COMPOUND OF THEFORMULA: